68例肛管直肠黏膜黑色素瘤临床病理特征及预后

doi:10.19723/j.issn.1671-167X.2023.02.009

摘要/Abstract

摘要：

目的: 总结肛管直肠黏膜黑色素瘤(anorectal mucosal melanoma, ARMM)的临床病理特征, 分析其预后相关因素。方法: 回顾性分析2010—2018年北京大学肿瘤医院收治的原发性ARMM手术切除标本共68例, 复阅病理切片评估病理特征, 分期采用Slingluff分期法。结果: (1) 临床特征: 患者诊断时中位年龄61.5岁, 男女比例1 ∶1.62, 首发临床表现最常见的是便血(49例); 肿瘤部位最常见的是肛管直肠(66.2%), 其次为直肠(20.6%); 诊断时分期为Ⅰ期28例(局限期, 41.2%), Ⅱ期25例(区域淋巴结转移期, 36.8%), Ⅲ期15例(远处转移期, 22.1%); 5例行局部扩大切除术, 其余为腹会阴联合切除术, 48例术后接受了辅助治疗。(2)病理特征: 大体检查88.2%为隆起型肿块, 肿瘤中位最大径3.5 cm, 中位厚度1.25 cm, 黏膜肌以下浸润深度0~5.00 cm(中位1.00 cm); 肿瘤浸润达固有肌层者27例, 达肠周脂肪组织者16例; 67.6%为无色素性或色素不明显; 细胞形态最常见的是上皮样(45例, 66.2%); 89.7%有溃疡形成, 35.3%可见坏死, 55.9%有血管淋巴管侵犯, 30.9%有神经周围侵犯, 核分裂象计数中位值18/mm²; 免疫组织化学检测S100、HMB-45和Melan-A阳性率分别为92.0%、92.6%、98.0%, Ki-67增殖指数中位值50%;53例进行了CKIT、BRAF及NRAS基因突变检测, 突变率分别为17.0%(9例), 3.8%(2例), 9.4%(5例)。(3)预后: 66例患者获得了随访资料, 中位随访17个月, 中位生存时间17.4个月, 1年、2年、5年的总生存率分别为76.8%、36.8%、17.2%;诊断时淋巴结转移率56.3%;49例(84.5%)发生了远隔部位转移, 最常见的转移部位是肝; 单因素分析显示, 肿瘤最大径(>3.5 cm)、黏膜肌以下浸润深度(>1.0 cm)、坏死、血管淋巴管侵犯、BRAF基因突变、术后未行辅助治疗、肿瘤浸润层次深、诊断时分期晚均为总生存期的预后不良因素; 多因素分析显示, 血管淋巴管侵犯、BRAF基因突变为影响总生存期的独立危险因素, 诊断时分期相关的P值接近临界值。结论: ARMM患者的总体预后差, 血管淋巴管侵犯、BRAF基因突变是独立的预后不良因素; Slingluff分期法可以有效提示预后, 诊断时应详尽评估病理特征, 明确分期, 并尽可能做基因检测; 肿瘤黏膜肌以下的浸润深度可能是比肿瘤厚度更好的预后指标。

关键词: 黏膜黑色素瘤, 肛管直肠肿瘤, 临床病理特征, 预后

Abstract:

Objective: To investigate the clinicopathological characteristics of anorectal mucosal melanoma (ARMM), and to evaluate the prognostic factors. Methods: A total of 68 primary ARMM surgical specimens from 2010 to 2018 were retrospectively studied. Slides were reviewed to evaluate pathological features. Slingluff staging method was used for staging. Results: (1) Clinical features: The median age at diagnosis in this group was 61.5 years, with a male-to-female ratio 1 ∶1.62. The most common complaint was blooding (49 cases). For anatomic site, anorectum was the prevalent (66.2%), followed by rectum (20.6%). At the time of diagnosis, 28 cases were stage Ⅰ (localized stage, 41.2%), 25 cases were stage Ⅱ (regional lymph node metastasis, 36.8%), and 15 cases were stage Ⅲ (distant metastasis, 22.1%). Five patients underwent wide local excision, the rest abdominoperineal resection, and 48 patients received adjuvant therapy after surgery. (2) Pathological features: Grossly 88.2% of the tumors were exophytic polypoid masses, with the median tumor size 3.5 cm and the median tumor thickness 1.25 cm. Depth of invasion below lamina muscularis mucosae ranged from 0-5.00 cm (median 1.00 cm). The deepest site of tumor invasion reached muscular layer in 27 cases, and perirectal tissue in 16 cases. Melanin pigmentation was absent or not obvious in 67.6% of the cases. The predominant cytology was epithelioid (45 cases, 66.2%). The rate for ulceration, necrosis, lymphovascular invasion, and perineural invasion was 89.7%, 35.3%, 55.9%, and 30.9%, respectively. The median mitotic count was 18/mm². The positive rate of S100, HMB-45 and Melan-A were 92.0%, 92.6% and 98.0%, respectively. The median of Ki-67 was 50%. The incidences of mutations within CKIT, BRAF and NRAS genes were 17.0% (9 cases), 3.8% (2 cases) and 9.4% (5 cases), respectively. (3) Prognosis: Survival data were available in 66 patients, with a median follow-up of 17 months and a median survival time of 17.4 months. The 1-year, 2-year and 5-year overall survival rate was 76.8%, 36.8% and 17.2%, respectively. The rate of lymphatic metastasis at diagnosis was 56.3%. Forty-nine patients (84.5%) suffered from distant metastasis, and the most frequent metastatic site was liver. Univariate analysis revealed that tumor size (>3.5 cm), depth of invasion below lamina muscularis mucosae (>1.0 cm), necrosis, lymphovascular invasion, BRAF gene mutation, lack of adjuvant therapy after surgery, deep site of tumor invasion, and high stage at diagnosis were all poor prognostic factors for overall survival. Multivariate model showed that lymphovascular invasion and BRAF gene mutation were independent risk factors for lower overall survival, and high stage at diagnosis showed borderline negative correlation with overall survival. Conclusion: The overall prognosis of ARMM is poor, and lymphovascular invasion and BRAF gene mutation are independent factors of poor prognosis. Slingluff staging suggests prognosis effectively, and detailed assessment of pathological features, clear staging and genetic testing should be carried out when possible. Depth of invasion below lamina muscularis mucosae of the tumor might be a better prognostic indicator than tumor thickness.

Key words: Mucosal melanoma, Anorectal tumor, Clinicopathological features, Prognosis

中图分类号:

R735.3

赖玉梅,李忠武,李欢,吴艳,时云飞,周立新,楼雨彤,崔传亮. 68例肛管直肠黏膜黑色素瘤临床病理特征及预后[J]. 北京大学学报（医学版）, 2023, 55(2): 262-269.

Yu-mei LAI,Zhong-wu LI,Huan LI,Yan WU,Yun-fei SHI,Li-xin ZHOU,Yu-tong LOU,Chuan-liang CUI. Clinicopathological features and prognosis of anorectal melanoma: A report of 68 cases[J]. Journal of Peking University (Health Sciences), 2023, 55(2): 262-269.

图/表 4

表1

68例肛管直肠黏膜黑色素瘤的临床病理特征"

Features	Value	Features	Value
Gender		Pigmentation
Male	26 (38.2%)	Obvious	22 (32.4%)
Female	42 (61.8%)	Not obvious	46 (67.6%)
Age/years		Cytology^*
Median (range)	61.5 (43.0-99.0)	Epithelioid	45 (66.2%)
Anatomic site		Spindled	19 (27.9%)
Rectum	14 (20.6%)	Nevoid	22 (32.4%)
Anorectum	45 (66.2%)	Polymorphic	7 (10.3%)
Anal canal	9 (13.2%)	Ulceration
Stage at diagnosis		Yes	61 (89.7%)
Ⅰ	28 (41.2%)	No	7 (10.3%)
Ⅱ	25 (36.8%)	Necrosis
Ⅲ	15 (22.1%)	Yes	24 (35.3%)
Therapy		No	44 (64.7%)
Surgery only	20 (29.4%)	Lymphovascular invasion
Adjuvant therapy after surgery	48 (70.6%)	Yes	38 (55.9%)
Surgery		No	30 (44.1%)
WEL	6 (8.8%)	Perineural invasion
APR	62 (91.2%)	Yes	21 (30.9%)
Tumor size/cm		No	47 (69.1%)
Median (range)	3.5 (0.5-8.5)	Mitosis (per mm²)
≤2.0	13 (19.1%)	Median (range)	18 (2-59)
2.1-4.0	33 (48.5%)	≤10	17 (25.0%)
4.1-6.0	14 (20.6%)	11-20	26 (38.2%)
≥6.1	8 (11.8%)	21-30	14 (20.6%)
Tumor thickness/cm		≥31	11 (16.2%)
Median (range)	1.25 (0.06-5.00)	TILs
≤1.0	24 (35.3%)	Brisk	9 (13.2%)
1.1-2.0	38 (55.9%)	Non-brisk	59 (86.8%)
≥2.1	6 (8.8%)	Ki-67 (32 cases)
Depth of invasion below lamina muscularis mucosae/cm		Median(range)	50% (10%-90%)
Median (range)	1.0 (0-5.0)	Gene mutations (53 cases)
≤1.0	35 (51.5%)	CKIT mutation	9 (17.0%)
1.1-2.0	29 (42.6%)	BRAF mutation	2 (3.8%)
≥2.1	4 (5.9%)	NRAS mutation	5 (9.4%)
Deepest site of tumor invasion		Wild types	37 (69.8%)
Lamina propria	2 (2.9%)
Submucosa	23 (33.8%)
Muscular layer	27 (39.7%)
Perirectal tissue	16 (23.5%)

表1

图1

表2

单因素分析66例肛管直肠黏膜黑色素瘤与总生存期相关的预后因素"

Features	No. of cases	No. of death	Median survival/months	95%CI	χ²	P value
All patient	66	53	17.433	16.198-18.668
Gender
Male	26	21	19.300	5.203-33.397
Female	40	32	16.733	14.090-19.377	0.168	0.682
Age
≤61.5 years old	33	27	19.000	13.130-24.870
>61.5 years old	33	26	16.633	11.607-21.659	0.240	0.624
Anatomic site
Rectum	12	8	12.933	6.926-18.940
Anorectum	45	37	16.733	12.479-20.988
Anal canal	9	8	34.667	29.115-40.218	0.669	0.716
Stage at diagnosis
Ⅰ	27	18	33.300	8.835-57.765
Ⅱ	24	22	16.733	10.672-22.794
Ⅲ	15	13	12.333	10.113-14.554	13.226	0.001^*
Therapy
Surgery only	18	17	14.100	8.326-19.874
Adjuvant therapy after surgery	48	36	19.000	10.371-27.629	7.361	0.007^*
Surgery
WEL	6	4	18.533	12.652-24.415
APR	60	49	17.267	15.003-19.531	0.687	0.407
Tumor size
≤3.5 cm	36	25	29.033	9.522-48.545
>3.5 cm	30	28	12.933	11.934-13.933	8.607	0.003^*
Tumor thickness
≤1.25 cm	32	25	21.700	16.196-27.204
>1.25 cm	34	28	13.100	12.032-14.168	1.494	0.222
Depth of invasion below lamina muscularis mucosae
≤1.0 cm	34	23	32.767	16.767-48.766
>1.0 cm	32	30	12.767	11.736-13.797	13.189	< 0.001^*
Deepest site of tumor invasion
Lamina propria or submucosa	25	14	34.667	15.019-54.314
Muscular layer	25	24	17.433	14.822-20.045
Perirectal tissue	16	15	11.067	6.940-15.193	27.037	< 0.001^*
Pigmentation
Not obvious	44	33	19.000	12.744-25.256
Obvious	22	20	13.533	6.041-21.026	2.804	0.094
Ulceration
Yes	59	47	17.267	15.024-19.510
No	7	6	42.133	18.096-66.170	1.072	0.300
Necrosis
Yes	23	21	12.933	11.828-14.038
No	43	32	25.100	10.006-40.194	20.243	< 0.001^*
Lymphovascular invasion
Yes	37	34	13.533	8.783-18.284
No	29	19	32.767	18.918-46.616	10.003	0.002^*
Perineural invasion
Yes	21	19	12.933	11.692-14.175
No	45	34	19.000	17.128-20.872	3.171	0.075
Mitosis
≤18/mm²	35	27	22.467	13.117-31.816
>18/mm²	31	26	13.533	9.084-17.983	3.855	0.050
TILs
Brisk	8	8	18.333	10.387-26.279
Non-brisk	58	45	17.267	14.467-20.066	0.146	0.703
Ki-67 (31 cases)
≤50%	17	14	18.533	14.027-23.040
>50%	14	9	29.033	0.000-58.490	1.587	0.208
Gene mutations (52 cases)
CKIT mutation	8	7	17.267	9.505-25.028
BRAF mutation	2	2	3.700
NRAS mutation	5	5	16.200	9.186-23.214
Wild types	37	28	18.333	14.651-22.016	32.244	< 0.001^*

表2

表3

参考文献 26

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Features	HR value	95%CI	P value
Stage at diagnosis
Ⅱ vs. Ⅰ	1.995	0.742-5.362	0.171
Ⅲ vs. Ⅰ	2.790	0.941-8.272	0.064
Therapy (adjuvant therapy after surgery vs. surgery only)	0.647	0.282-1.482	0.303
Tumor size (>3.5 cm vs. ≤3.5 cm)	1.755	0.796-3.872	0.164
Depth of invasion below lamina muscularis mucosae (>1.0 cm vs.≤1 cm)	1.027	0.407-2.592	0.954
Deepest site of tumor invasion	1.091	0.573-2.075	0.791
Muscular layer vs. lamina propria or submucosa	1.332	0.535-3.316	0.538
Perirectal tissue vs. lamina propria or submucosa	1.542	0.383-6.203	0.542
Lymphovascular invasion (yes vs. no)	2.929	1.261-6.804	0.012
Gene mutations
CKIT mutation vs. wild types	1.543	0.576-4.132	0.388
BRAF mutation vs. wild types	110.292	12.244-993.515	< 0.001
NRAS mutation vs. wild types	2.311	0.731-7.311	0.154

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